2-Alpha-carboxy-3-alpha(hydroxyethyl)-5-oxocyclopentane derivatives

ABSTRACT

This invention relates to a new and novel synthesis of Prostaglandin E1 and more particularly to a synthesis which has a high degree of stereoselectivity at the points of generating the asymmetric centers of the molecule. It relates further to a synthesis in which the yields are high in the several reaction steps. The invention relates still further to the novel compounds obtained as intermediates in the prostaglandin E1 synthesis and the process for making such intermediates.

United States Patent Kuo et al.

June 24, 1975 I75] Inventors: Chan-Hwa Kuo, South Plainfield;

David Taub. Metuchen; Norman L. Wendler. Summit. all of NJ.

[73] Assignee: Merck & 0).. inc.. Rahway. NJ.

[22] Filed: Oct. 15, 1973 {2i} App]. No.: 406.714

Related US. Application Data [62] Division of Scr. No, 290.590. Sept.20. 1972. Pat.

[52] US. Cl. 260/3409 [Sl] Int. Cl C07d 13/04 [58] Field of Search260/3409 [56] References Cited UNITED STATES PATENTS 3.736.335 5/1973Wcndlcr ct al. 260/3409 3.833.612 9/1974 Wcndlcr et ul. 260/340,)

Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. WintersArmrney. Agent. or Firm-David L. Rose; Thomas E. Arther; Harry E.Westlake. Jr.

[57] ABSTRACT This invention relates to a new and novel synthesis ofProstaglandin E and more particularly to a synthesis which has a highdegree of stereoselectivity at the points of generating the asymmetriccenters of the molecule. It relates further to a synthesis in which theyields are high in the several reaction steps. The in vention relatesstill further to the novel compounds obtained as intermediates in theprostaglandin E synthesis und the process for making such intermediates.

6 Claims, No Drawings Z-ALPHA-CARBOXY-li- ALPHA(HYDROXYETHYL)-5-OXOCYCLOPENTANE DERIVATIVES This is a division of application Ser. No;290,590, filed Sept. 20, 1972, now US. Pat. No. 3,850,952.

DETAILED DESCRIPTION OF THE lNVENTlON Prostaglandin E which may bedepicted structurally H ii l O l O oo 0/ (CH2) -coon -a ll (CH -COOR231-273, Pergamon Press (l968).

One of the more important prostaglandins is prostaglandin E also knownas PGE,. It has an effect on the contractility of smooth muscle and isuseful in the induction of labor in pregnant females and for thetermination of pregnancies by therapeutic abortion, M.P. Embrey, BritishMedical Journal, I970, 2, 256-258; 258-260. Other uses, besidesstimulation of smooth muscle, are described in the literature andinclude the lowering of blood pressure, effect on the mobilization offree fatty acids from adipose tissue, inhibition of lipolysis, andbronchodilating effects.

Heretofore, the supply of prostaglandin E,, as well as of otherprostaglandins, has been severly limited because only minute amounts ofnaturally occurring material are available, and partial biosynthesis byenzymes present in mammalian seminal vesicles has only afforded limitedamounts of the products.

An object of this invention is to provide a facile and economicsynthesis of racemic prostaglandin E which compound has one-half thebiological activity of the naturally occurring PGE,.

A further object of the invention is to provide novel intermediatecompounds some of which in addition to being useful in the synthesis ofracemic (i) PGE,, may themselves exhibit prostaglandin-like activity. Anadditional object is to provide a stereoselective total synthesis of theother members of the prostaglandin group which may be prepared by knownmethods from (i) prostaglandin E,. Thus, for instance, (1) prostaglandinF may be obtained by reduction of (i) POE Other objects will becomeevident from the following description of the invention. The novelprocess and intermediates of our invention are shown structurally in thefollowing flow diagram, and immediately following this diagram thechemical names of the compounds are set forth.

B (CH COOP.

ll 0= I b H -COOR III (CH -COOH IV v in the foregoing formulae R isloweralkyl or aralkyl; and R is a halogen, l-imidazolyl, carbazolyl,aziridinyl, or 3,5-dimethylpyrazolyl. The loweralkyl groups of thisinvention are those containing from I to 6 carbon atoms such as methyl.ethyl, propyl, and hexyl. The aralkyl groups are defined as loweralkylgroups substituted with an aromatic group of from 6 to ID carbon atoms.Preferred are benzyl, xylyl and the like. The term *halogen includes theatoms fluorine, chlorine, bromine, and iodine.

As a matter of convenience for understanding the foregoing flowsheet andthe following description of the invention, there follows a list ofnames of the chemical compounds A, B, and l-XVl inclusive. A R,-8,lo-undecadienoate B Bangelicalactone I 6a- Carboxy-5a-( l-hydroxyethyl)2-cyclohexenel heptanoic acid loweralkyl or aralkyl ester, 'y-lactone.ll 3-Carboxymethyl-4-methyl-2-[ l-carboxy-7- (loweralkoxy or aralkoxycarbonyl)heptyl1-4- hydroxybutyric acid 'y-lactone. IllZa-Carboxy-Bal-hydroxyethyl )-5-oxocyclopentaneheptanoic acid loweralkylor aralkyl ester, y-lactone. IV 2a- Carboxy-3a-( 1-hydroxyethyl)-5-oxocyclopentaneheptanoic acid loweralkyl or aralkyl ester, 'y-lactoneS-cyclic ethylene acetal. V 2a- Carboxy-3a-( l-hydroxyethyl )-5-oxocyclopentaneheptanoic acid S-cyclic ethylene acetal, y-lactone. VI2a-Carboxy-3a-( l-hydroxyethyl)- l-(6-R-carbonylhexyl)-5-cyclopentanone, 5 cyclic ethylene acetal, -y-lactone.Vll 2a-Carboxy-3a-( lhydroxyethyl l o-formylhexyl )-5-cyclopentanone,S-cyclic ethylene acetal, y-lactone. Vlll 2a- Carboxy-3a-(l-hydroxyethyl)-l -{6-( l ,3-dioxolan-2- yl)hexyl]-5-cyclopentanoneS-cyclic ethylene acetal, 'y-lactone. [X 2a-Carboxy-3a-(l,l,dihydroxyethyl)- 5-oxocyclopentaneheptanoic acid, carboxymethylester, 'y-lactone S-cyclic ethylene acetal. X 3B-Acetyl-2a-carboxy-5-oxolB-cyclopentaneheptanoic acid, loweralkyl or aralkylester S-cyclic ethylene acetal. Xl 3B-Acetoxy-Za-carboxy-S-oxol B-cyclopentaneheptanoic acid, loweralkyl or aralkyl ester S-cyclicethylene acetal. Xll 3B-Acetoxy2mR carbonyl-S-oxo-lB-cyclopentaneheptanoic acid loweralkyl or aralkyl ester S-cyclicethylene acetal. Xlll BB-Acetoxy-Zwformyl-S-oxo- IB-cyclopentaneheptanoic acid loweralkyl or aralkyl ester S-cyclic ethyleneacetal. XIV 3B-Acetoxy-5-oxo-2a- (3-oxol -octenyllB-cyclopentaneheptanoic acid, loweralkyl or aralkyl ester S-cyclicethylene acetal. XV 3B-Acetoxy-5-oxo-2a-(3-hydroxy-1-octenyl)- 1B-cyclopentaneheptanoic acid, loweralkyl or aralkyl ester S-cyclicethylene acetal. XVI Prostaglandin E,.

The synthesis of (i) prostaglandin E. starts with the condensation of R-8, IO-undecadienoate (A) and B-angelicalactone (B) in a Diels-Alderreaction. The reaction is generally run in a closed reaction vessel withthe preferred temperature in the l50250C. range. A solvent is optionalas the reaction is readily performed without one, however, if one isemployed a nonreactive aprotic solvent is preferred. In general,however, the only need for a solvent is to facilitate the transfer ofthe reactants into the reaction vessel. The reaction is generallycomplete in from 5 to 50 hours in the above temperature range.Preferably the reaction is run at from 20 to 30 hours at l75-225C. Thesubstrates react in equimolar quantities but it is preferred, in orderto improve the yield based on R -8, 10- undecadienoate, to maintain anexcess of fi-angelicalactone over the R -8, lO-undecandienoate.Generally up to a 5 molar excess of the lactone is sufficient. Theexcess lactone is recovered from the reaction mixture and is reusable.

The Diels-Alder adduct, 6a-carboxy-50z(lhydroxyethyl)-2-cyclohexene-l-heptanoic acid loweralkyl or aralkylester -y-lactone (l) is treated with an oxidizing agent capable ofselectively cleaving an olefinic bond in order to oxidatively cleave thecyclohexene double bond and form the dicarboxylic acid, viz 3-carboxymethyl4-methyl-2-[ l-carboxy7-( loweralkoxy or aralkoxycarbonyl)heptyl]-4-hydroxybutyric acid 'y-lactone (II). The oxidizingagents of choice are ozone, potassium permanganate, sodiumperiodatepotassium permanganate and the like. Ozonolysis is thepreferred procedure. Owing to the reactivity of ozone the reaction isrun at a depressed temperature of from 20 to C. The ozonide intermediateis decomposed by treatment with hydrogen peroxide in acetic acid at from2575C. The product (II) is isolated by techniques known to those skilledin this art.

The oxidation product, 3-carboxymethyl-4-methyl-2-l-carboxy-7-(loweralkoxy or aralkoxy carbonyl)heptyll-4-hydroxybutyricacid y-lactone (H) is decarboxylated and ring closed affording2a-carboxy-3a-( lhydroxyethyD-S-oxocyclopentaneheptanoic acid loweralkylor aralkyl ester, y-lactone (ill). The dicarboxylic acid is treated withan acid anhydride such as acetic anhydride and a base which is thealkali metal salt of the carboxylic acid corresponding to the acidanhydride such as sodium acetate. When acetic anhydride is the reactantalong with the ketone (III) is formed in enol acetate derivativethereof:

CH CO0- (CH *COOR (III-A) The enol acetate may be hydrolyzed to thedesired ketone (III) by acid catalyzed hydrolysis with, for exam ple,hydrochloric acid in a loweralkanol. This will afford pure ketone (Ill).However, the mixture of (III) and (Ill-A) may be reacted together in thepreparation of the cyclic ethylene acetal derivative, 2a-carboxy-3a- I-hydroxyethyl )-5-oxocyclopentaneheptanoic acid loweralkyl or aralkylester, 5-cyclic ethylene acetal, -y-lactone (IV) by treatment withethylene glycol and preferably also with an acid catalyst such asp-toluenesulfonic acid monohydrate. Both the ketone group of (ill) andenol acetate of (Ill-A) are simultaneously converted to the cyclicethylene acetal function. The reaction is preferably run in a solventwhich is not miscible with water such as benzene or toluene which formsan azeotrope therewith which is separable therefrom in a suitableapparatus. In this way the progress of the reaction may be followed byobserving the molar quantities of water produced during the reaction.When the calculated amount of water is removed, the reaction iscomplete. The cyclic acetal is isolated by procedures known to oneskilled in this art.

The carboxylic ester function of 2a-carboxy-3a-(lhydroxyethyl)-5-oxocyclopentaneheptanoic acid loweralkyl or aralkylester S-cyclic ethylene acetal, 'y-lactone (IV) is hydrolyzed to thecarboxylic acid by base catalyzed hydrolysis in a solvent such as analkali metal hydroxide in a loweralkanol. Acid catalyzed hydrolysiscannot be employed in as much as this will cause the hydrolysis of thecyclic acetal also. The reaction is run generally at room temperaturealthough slight cooling or heating will not adversely affect thereaction. A temperature range of l35C. is permitted with the reactionbeing complete in from minutes to 3 hours. 2a- Carboxy-3a-(l-hydroxyethyl)-S- oxocyclopentaneheptanoic acid ethylene acetal,'y-lactone (V) is isolated by the usual techniques.

The next step in the synthesis is the reduction of the carboxylic acidgroup to the aldehyde group. This is accomplished by first replacing thehydroxyl function of the carboxylic acid group of 2a-carboxy-3a-( 1-hydroxyethyl)-5-oxocyclopentaneheptanoic acid 5- cyclicethylene acetal,ylactone (V) with a suitable leaving group such as an imidazole,carbazole, aziridine, or 3,5-dimethyl pyrazole groups, a halide or thelike. It is preferred to form the imidazolyl and the like derivativeswith reagents as N,N'carbonyldiimidazole. The reaction is run in anon-hydroxylic solvent such as tetrahydrofuran, either, benzene, and thelike at from l035C. for a duration of from 1 to 4 hours. The halides areformed from the alkali metal salt of compound V with the use of an acidhalide under moderate conditions such that the cyclicethylene acetal isnot destroyed. The reaction is run at from l0 to lOC. for from 5 minutesto 1 hour. The preferred halide is chlorine and the preferred reagent isoxalyl chloride.

The protected intermediate 2a-carboxy-3a-( lhydroxyethyl l 6-R--carbonylhexyl )-5- cyclopentanone, S-cyclic ethylene acetal, -y-lactone(VI) is reduced by treatment with a moderate reducing agent such aslithium tri-t-butoxy aluminum hydride, lithium borohydride and the like,although the former reducing agent is preferred. The reduction is run inan inert non-reducible solvent such as tetrahydrofuran, ether, ethyleneglycol dimethyl ether, and the like. The reaction is generally completein from I to 6 hours at from 80 to C. although the reaction is preferredto be run substantially at from 25 to 25C. The product is isolated andpurified by techniques known to one skilled in this art.

The side-chain aldehyde group of 2a-carboxy-3a-( lhydroxyethyl l-(6-formy1hexyl )-5-cyclopentanone S-cyclic ethylene acetal, y-lactone(Vll) is protected by forming the cyclic ethylene acetal derivativethereof, viz 2a-carboxy-3a-( l-hydroxyethyl)- l -[6-( 1,3-dioxolan-2-yl)hexyl]-5-cyclopentanone 5-cyclic ethylene acetal,y-lactone (VIII). The procedure is sbstantially the same as thatemployed in preparing 2acarboxy-3a-( l-hydroxyethyl )-5-oxocyclopentaneheptanoic acid S-cyclic ethylene acetal, 7-lactone,loweralkyl or aralkyl ester (IV) discussed above, and the discussionneed not be repeated.

The next step consists of saponification of the lactone to the alkalimetal salt of the corresponding hydroxy acid followed by oxidation ofthe hydroxy group thereof as well as the simultaneous oxidation of theterminal side chain function forming 2a-carboxy-3a-( l ldihydroxyethyl)-5-oxocyclopentaneheptanoic acid, carboxymethyl ester(y-lactone) S-cyclic ethylene acetal, (IX). The y-Iactone is opened withbase catalysis using an alkali metal hdroxide carbonate such as sodiumhydroxide, potassium hydroxide, sodium carbonate and the like. A solventis generally employed and a loweralkanol is preferred. Sodium hydroxidein methanol is most preferred. The hydrolysis is generally complete infrom I to 10 hours at from 040C. The progress of the hydrolysis isfollowed by taking a thin layer chromatogram of the reaction mixture.When the starting material has disappeared the reaction is complete. Theproduct from the hydrolysis is not isolated but rather the loweralkanolsolvent is exchanged for water and the resultant aqueous solution at apH of from 7-9 treated with an oxidizing agent such as progresstetroxide prepared from ruthenium dioxide and sodium periodate. Thepregress of the reaction is followed by the formation of the yellowsolution of ruthenium tetroxide and, as the oxidation procedes, thereformation of the black precipitate of ruthenium dioxide. The reactionis complete when there is no further production of ruthenium dioxide.Any excess ruthenium tetroxide can be destroyed by the dropwise additionof a Ioweralkanol or other readily oxidizable substance which, however,must not interfere with or react with the product 2a-carboxy-3oz-( l ldihydroxyethyl )-5-oxocyclopentaneheptanoic acid methyl ester(y-lactone) S-cyclic ethylene acetal (IX). The product is isolated bytechniques known in this art.

The lactone ring of 2a-carboxy-3a-(Lldihydroxyethyl)-5-oxocyclopentaneheptanoic acid carboxy methyl ester(y-lactone)-5-cyclic ethylene acetal is opened by treatment with analkali metal loweralkoxide or aralkoxide in the presence of thecorresponding alkanol, sodium methoxide in methanol being preferred.There results initially the preparation of the 3a-acetyl-2a-carboxylate(IX-A) viz:

(CH C 0 CH COOH I X-A The 3a-acetyl group of lX-A is then epimerized andester interchange of the terminal glycolic acid residue with thealkoxide function present in the reaction mixture takes place, affording3B-acetyl-2a-carboxy-S- oxo-lB-cyclopentaneheptanoic acid, loweralkyl oraralkyl ester, S-cyclic ethylene acetal (X). The above steps all occurin situ and intermediate lX-A is not isolated. The reaction is runsubstantially at room temperature l 5-35C.) for from 5 to 25 hours, andthe product purified by known techniques. 3B-Acetyl-2a-carboxyl-5*oxo-I18- cyclopentaneheptanoic acid, loweralkyl or aralkyl ester S-cyclicethylene acetal (X) is oxidized in a Bayer- Villiger reaction using anorganic paracid such as trifluoroperacetic acid, m-chloroperbenzoic acidand the like affordingZia-acetoxy-2a-carboxy-5-oxolacyclopentaneheptanoic acid, loweralkyl oraralkyl ester (XI) S-cyclic ethylene acetal. The reaction mixture isgenerally buffered with alkaline buffering agents such as sodiummonohydrogenphosphate. The reaction is initially maintained at from l()to 10C., and when all of the reagents are combined the temperature ofthe reaction mixture is raised to from 2040C. for from l-6 hours. Theprogress of the reaction is followed with the aid of thin layerchromatography. Additional peracid may be added if the reaction isobserved to have stopped before reaching completion.

The carboxylic acid group of3B-acetoxy-2acarboxyS-oxo-IB-cyclopentaneheptanoic acid. loweralkyl oraralkyl ester 5-cyclic ethylene acetal (X) is reduced to the aldehydegroup though the imidazolyl, halo, carbazolyl, aziridinyl, or3,5-dimethylpyrazolyl intermediates (XII) affording3B-acetoxy2a-formyl-5- oxo-lB-cyclopentaneheptanoic acid, loweralkyl oraralkyl ester 5-cyclic ethylene acetal, (XIII). The procedure isgenerally the same as the preparation of the intermediate (VI) andaldehyde (VII) and the discussion need not be repeated.

The aldehyde 3B-acet0xy-2a-formyl-5-oxo-1B- cyclopentaneheptanoic acid,loweralkyl or aralkyl ester 5-cyclic ethylene acetal (XIII) is reactedwith dilowera 1kyl-2-oxoheptylphosphonate under the conditions of aWittig reaction to form 3B-acetoxy-5-oxo-2a-(3-oxo-1-octenyl)-lB-cyclopentaneheptanoic acid loweralkyl or aralkyl ester5-cyclic ethylene acetal, (XIV).

3B-Acetoxy-2a-formyl-5-oxo-1B- cyclopentaneheptanoic acid, loweralkyl oraralkyl ester S-cyclic ethylene acetal, (XIII) and 3B-loweralkanoyloxy-S-oxo-2oz-(3-oxo-1-octenyl)-1B- cyclopentaneheptanoicacid, loweralkyl or aralkyl ester S-cyclic ethylene acetal, (XIV) areknown precursors of prostaglandin E are described in copending U.S. Pat.application Ser. No. 48,548 filed June 22, 1970 along with proceduresfor converting said compounds to POE (XVI).

In order that this invention may be more fully understood the followingexamples are presented, which examples are given for purposes ofillustration and not of limitation.

PREPARATION A Methyl-8, 1 O-undecadienoate To a solution of allyltriphenylphosphonium bromide (38.4 g.) in 500 ml. of ether stirred underN is added 58 ml. of 1.7 M n-butyl lithium in hexane over 5 minutes.After 20 minutes the stirred mixture is cooled to C. and 17.0 g. ofmethyl 8-oxo-octanoate in 100 ml. of ether is added over 30 minutes,resulting in discharge of the red ylid color. The mixture is tirred 90minutes at room temperature, filtered, and the precipitate washed wtihether. The combined filtrate and washings are washed with water,saturated aqueous sodium chloride, dried over MgSO and concentrated todryness under vacuum. Distillation of the residue 14.3 g.) at 0.05 mm.gives methyl undeca -8,l0 dienoate (7.0 g.) b.p. 6570/0.05 mm. k fl 226mm. (26,700).

EXAMPLE 1 6a-Carboxy-5a-( l-Hydroxyethyl)-2-Cyclohexene-1- HeptanoicAcid Methyl Ester, 'y-lactone A solution of methyl 8,10-undecadienoate(8.34 g.) and B-angelicalactone (20.8 g.) is heated in a glasslinedautoclave at 200 for 24 hours. The resulting yellow oil is dissolved indichloromethane and washed with 5% aqueous sodium bicarbonate, saturatedsalt solution, dried over MgSO and concentrated under vacuum to removeexcess B-angelicalactone and cis-diene. The residue (10.92 g.) ischromatographed on 300 g. of silica gel, eluting with 2% acetone inchloroform affording 6.94 g. (70%) of 6a-carboxy-5oz-( 1-hydroxyethyl)-2-cyclohexene- 1 -heptanoic acid methyl ester, 'y-lactone.A f' 5.68, 5.78. S 1.37 (d, j=7), 2.77 (m, 1H), 3.66 (s, 3H), 4.20 (m,1H), 5.6-6.0 (m, 2H).

EXAMPLE 2 3-Carboxymethyl-4'Methyl-2-[ l-Carboxy-7-(Methoxycarbonyl)Heptyl ]--y-Butyrolactone A stream of 3% ozone in oxygen is passedthrough a solution of the Diels Alder adduct: 6a-carboxy-5a-(lhydroxyethyl)-2-cyclohexene-l-heptanoic acid methyl ester, 'y-lactone(5.0 g. 0.0169 moles) in ml. of dichloromethane at about 60C. until thereaction mixture is saturated with ozone.

The excess ozone is removed in a stream of nitrogen and dichloromethaneis removed under reduced pressure to yield the ozonide as a colorlessfoam after flushing with benzene and ether. The ozonide is dissolved in150 ml. of acetic acid and 40 ml. of 30% hydrogen peroxide and themixture is heated at 55C. under nitrogen for 24 hours. The mixture isevaporated in vacuo at a bath temperature of less than 50C., flushedwith a nheptane-toluene mixture and the residue extracted into ethylacetate. The organic extract is washed with cold Nal-ISO; solution, 5%NaHCO salt solution, dried over MgSO, and concentrated to give 588 mg.of neutral material. The bicarbonate solution is acidified withsaturated NaI-I PO solution and extracted wtih ethyl acetate. The latterextract is washed with salt solution, dried over MgSO and evaporated togive 3.8 g. (72%) of the crystalline dicarboxylic acid3-carboxymethyl-4- methyl-2-[ 1-carboxy-7-(methoxycarbonyl) heptyl]--ybutyrolactone, m.p. 14l143 A 2.7-3.0, 5.65, 5.75, 5.80 lufi f 'a1.43 (d, j=7), 3.67 (s, 3H), 4.47 (m, 1H), 10.17 (s, 2H).

EXAMPLE 3 2a-Carboxy-3a-( l-Hydroxyethyl )-5- OxocyclopentaneheptanoicAcid Methyl Ester, 'y-Lactone A solution of 3-carboxymethyl-4-methyl-2-11- carboxy-7-( methoxycarbonyl )heptyl --y-butyrolactone (1.33 g., 3.71m moles) in 33 ml. of acetic anhydride is refluxed under nitrogen for1.5 hours. Anhydrous sodium acetate (2.0 g.) is added and the reactionmixture refluxed for an additional 1.5 hours. After cooling to roomtemperature, sodium acetate is removed by filtration and the mixture isevaporated in vacuo to near dryness after flushing several times with an-heptane toluene mixture. The last trace of acetic anhydride is removedby cautious addition of a small amount of methanol and again pumping todryness. The residue is dissolved in dichloromethane and washed with 5%aqueous NaHCO saturated salt solution, dried over MgSO and evaporated to1.18 g. ofa residue consisting of the ketone III and its correspondingenol acetate Ill-A with the former predominating as evidenced by tlc (5%acetone in chloroform) with (Ill-A) being more mobile. The conversion ofthe enol acetate to the ketone is achieved via acid hydrolysis bydissolving the above mixture in 30 ml. of 1.8% methanolic hydrogenchloride. After 16 hours at 25, the reaction mixture is com centrated invacuo to provide 1.086 g. of 2a-carboxy- 3a-(1-hydroxyethyl)-5-oxocyclopentaneheptanoic acid methyl ester,'y-lactone; A f' 5.66, 5.72, 5.78, fi a 1.43 (d, J=7) 3.66 (s.3 H,) 4.40(m,1H).

EXAMPLE 4 2a-Carboxy-3a-( l-Hydroxyethyl )-5- OxocyclopentaneheptanoicAcid Methyl Ester, 'y-Lactone, S-Cyclic Ethylene Acetal A mixture of1.184 g. of 2a-carboxy-3a-carboxy-3a- 1 -hydroxyethyl)-5-oxocyclopentaneheptanoic acid methyl ester, 'y-lactone, 3.94 ml. ofethylene glycol, 43 mg. of p-toluenesulfonic acid monohydrate in 100 ml.of benzene is azeotropically distilled with a Dean-Stark water separaterfor 16 hours. The reaction mixture is cooled and quenched into excessaqueous NaHCO solution. The layers are separated and the organic phaseis washed with water, saturated salt solution, dried over Na SO, andevaporated to dryness affording L308 g. of 2a-carboxy-3a-(l-hydroxyethyl)-5- oxocyclopentaneheptanoic acid methyl ester,y-lactone, S-cyclic ethylene acetal. y 5.68, 5.77, 10.52 fi f l L33 (d,J=7), 3.68 (S, 3H), 3.92 (S,4H), 4.42 (m, 1H).

EXAMPLE 5 2a-Carboxy-3a-( l-Hydroxyethyl )-5- OxocyclopentaneheptanoicAcid 5-Cyclic Ethylene Acetal, 'y-Lactone To a stirred solution of2a-carboxy-3a-( lhydroxyethyl)-5-oxocyclopentaneheptanoic acid methylester, -y-lactone, 5-cyclic ethylene acetal 1.0 g., 2.94 m moles) in 5ml. methanol is added 5.88 ml. of [N NaOH. The mixture is stirred at25C. for 1.5 hours. Methanol is removed at reduced pressure. The aqueousalkaline solution is poured into saturated aqueous NaH PO solution andextracted with ethyl acetate. The latter is extracted with 5% aqueousNaHCO The bicarbonate solution is chilled, acidified with solid NaH Pand extracted wtih ethyl acetate. The organic extract is washed withsalt solution, dried over Na SO and evaporated to provide 948 mg. (99%)of 2a carboxy-3a-( l-hydroxyethyl oxocyclopentaneheptanoic acid S-cyclicethylene acetal, 'y-lactone. A 2.83.l, 5.69, 5.78 (sh), 5.83, l0.55p.;nmr fi f 'a 1.38 (d, J=7), 3.93 (s, 4H), 4.45 (m, 1H), 8.40 (s, 1H).

EXAMPLE 6 2a-Carboxy-3a-( l-Hydroxyethyl l -(6-lmidazolylcarbonylhexyl)-5-Cyclopentanone, 5-Cyclic Ethylene Acetal,'y-Lactone N,N"Carbonyldiimidazole (1.24 g., 7.6 m moles) is added to astirred solution of 2a-carboxy-3a-(lhydroxyethyl)-5-oxocyclopentaneheptanoic acid 5- cyclic ethyleneacetal, y-lactone (2.36 (3., 7.26 m moles) in ml. of dry THF at 25C.under nitrogen. The reaction mixture is stirred at 25C. for 2 hours. Thesolvent is removed in vacuo and the oily residue is dissolved inbenzene, washed with water, saturated salt solution, and dried over NaSO and evaporated to afford 2.60 g. (98.5%) of2a-carboxy-3a-(1-hydroxyethyl)-l-(6-imidazolylcarbonylhexyl)-5-cyclopentanone, 5- cyclic ethylene acetal,'y-lactone. y f' 3.38, SASS-5.72, 6.55, 6.79, 7.05, 7.25, 1055p. S f 'Bl.36 (d, J=7), 3.92 (s, 4H), 4.46 (m, 1H) 7.07, 7.48, 8.18 (3H).

EXAMPLE 7 2oz-Carboxy-3a-( l-Hydroxyethyl)-l-(6-Formylhexyl)-5-Cyclopentanone, S-Cyclic Ethylene Acetal, -y-Lactone A solution oflithium tri-t-butoxy aluminum hydride (1.834 g., 7.2 m moles) in 45 ml.dry tetrahydrofuran is added dropwise to a stirred solution of (VI)(R,=imidizalolyl) (2.59 g., 6.87 m moles) in ml. of THF at 25 undernitrogen and the reaction mixture is stirred at 25 for 3 hours. At theend of this period, the solvent is removed under vacuum and to theresidue is added benzene and cold saturated aqueous Na SO solution.Inorganic salts are removed by filtration and the organic phase of thefiltrate is washed with water, saturated NaCl solution, dried over l\laSO and evaporated to yield 1.91 g. of 2a-carboxy-3a-( lhydroxyethyl)- l-(6-formylhexyl )-5-cyclopentanone, S-cyclic ethylene acetal, 'y-lactoneas an oil; A f' 3.70, 5.70, 5.8l, l0.55p.; fi a 1.36 (d, J=7), 3.90 (s,4H), 4.40 (m, 1H), 9.73 (t, 1H).

EXAMPLE 8 2a-Carboxy-3a-( l-Hydroxyethyl l -[6-( 1,3-Dioxolan- 2-yl)hexyl1-5-Cyclopentanone 5-Cyclic Ethylene Acetal, 'y-Lactone A mixtureof 2a-carboxy-3a( l-hydroxyethyl)-l-(6- formylhexyl)-5-cyclopentanone,5-cyclic ethylene acetal, -y-lactone (1.7 g.), p-toluenesulfonic acidmonohydrate (250 mg.) in ethylene glycol (25 ml.) and benzene ml.) isazeotropically distilled with a Dean- Stark water separater for 16hours. The mixture is cooled and added to excess chilled sodiumbicarbonate solution. The layers are separated and the aqueous phase isextracted wtih benzene. The combined organic extracts are washed withwater, saturated salt solution dried over Na SO and concentrated todryness under vacuum to give 1.91 g. of 2a-carboxy-3a-(lhydroxyethyl)-l-[6-( l ,3-dioxolan-2-yl)hexyl]-5- cyclopentanone5-cyclic ethylene acetal, y-lactone as thin needles, mp 4346C. A f'5.68, 10.55 6 f 'a 1.33 (d, J=7), 3.92 (m, 8H), 4.52 (m, 1H), 4.87 (t,1%, 1H).

EXAMPLE 9 2a-Carboxy-3a-( l,1-Dihydroxyethyl)-5-Oxocyclopentaneheptanoic Acid Carboxymethyl Ester, -y-Lactone 5-CyclieEthylene Acetal A solution of 2a-carboxy-3a-(1-hydroxyethyl)-l-[6-(l,3-dioxolan-2yl)hexylI-S-cyclopentanone S-cyclic ethylene acetal,y-lactone (1.0 g., 2.8 m moles), 20% aqueous NaOH (2.0 ml.) in 1.5 ml.of methanol is stirred at 25C. under a nitrogen atmosphere for 5 hoursat which time tlc indicated complete opening of the lactone ring. Themixture is concentrated in vacuo to remove the methanol and 1.5 ml. ofwater is added. The pH of the solution is adjusted to about 8 with astream of CO gas. Ruthenium dioxide (15 mg.) is then added to thestirred solution followed by dropwise addition of a solution of NalO.(2.772 g., 13.0 m moles) in 5-10 ml. of water. The progress ofthe redoxreaction is indicated by the formation of yellow homogeneous rutheniumtetroxide solution followed by reappearance of the black rutheniumdioxide precipitate. When the yellow color persists indicatingcompletion of the reaction, the excess oxidizing agent (RuO.,) isdestroyed by the addition of a few drops of isopropyl alcohol. Theresulting reaction mixture is added to excess cold aqueous NaH POsolution and extracted with ethyl acetate. The organic phase is washedwith water, saturated aqueous NaCl solution, dried over MgSO and evaporated to provide L067 g. of 2a-carboxy-3a-(l,ldihydroxyethyl-oxocyclopentaneheptanoic acid carboxymethyl ester,'y-lactone S-cyclic ethylene acetal, A f' 2.9. 5.69-5.80, l0.55pt;5 "s3.93 (s, 4H), 4.63 (s, 2H), 7.93 (broad S).

EXAMPLE l0 3B-Acetyl-2a-Carboxy-5-Oxol [3' Cyclopentaneheptanoic AcidMethyl Ester, S-Cyclic Ethylene Acetal To a solution of l g. of2a-carboxy-3a-(l,l-

dihydroxyethyl)-5oxo-cyclopentaneheptanoic acid carboxymethyl ester,'y-lactone S-cyclic ethylene acetal in 5 ml. of methanol is added 30 ml.of 0.88N sodium methoxide in methanol under an atmosphere of nitrogenand the reaction mixture is stirred at 25C. for 16 hours. The reactionmixture is quenched into excess, chilled, saturated NaH PO andconcentrated in vacuo to remove the methanol. The aqueous phase issaturated with salt and extracted with ethyl acetate. The latter extractis washed with salt solution, dried (MgSO and evaporated to give 945.4mg. (96.5%) of 3B-acetyl-2a-carboxy-5 -oxo-1B- cyclopentaneheptanoicacid methyl ester, S-cyclic ethylene acetal; A I" 2.8-3.3, 5.73 sh.,5.80 sh., 5.83, 10.52pt; 8 2.20 (s, 3H), 3.67 (s, 3H), 3.93 (s, 4H),9.37 (broad s, 1H).

EXAMPLE I l 3BAcetoxy-Za-Carboxy-S-Oxo- 1B- Cyclopentaneheptanoic AcidMethyl Ester S-Cyclic Ethylene Acetal Peroxytrifluoroacetic acid isprepared by the dropwise addition of 28 ml. of trifluoroacetic anhydrideto 4.4 ml. of 90% H in 40 ml. of dichloromethane at 0C.. The mixture isstirred at 25 for 30 minutes and stored at 0C. The titer is 1.4 M. Justbefore use l0 g. of powdered Na HPO. is added portionwise with stirringat 0C.

To a stirred solution of (883 mg.) of3B-acetyl-2acarboxy-5oxo-lB-cyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal in 17 ml. of dichloromethane at 0C. is added g.of powdered Na HPO, portionwise. Through a dropping funnel, 24.3 ml. theabove CF CO H solution in CH Cl is added dropwise during 5 minutes.After the addition is complete, the reaction mixture is allowed to warmto room temperature and stirring is continued for 6 hours. Thistreatment is then repeated after chilling the reaction mixture to 0C.and the final reaction mixture is stirred at 25C. under nitrogen for 16hours.

After removal of the inorganics by filtration, the fil trate is washedwith cold aqueous Kl solution followed by cold aqueous Na S O todischarge the iodine color, water, and saturated salt solution. Theorganic extracts are dried (MgSO and evaporated to give 712 mg. of3B-acetoxy-2a-carboxy-5oxo- 1B- cyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal as an oil. A 28-33, 5.75 sh., 5.80, 5.83 sh.,10.55 y a" 2.05 (s, 3H), 3.67 (s, 3H), 3.97 (s, 4H), 5.24 (m, 1H), 8.37(broad s, IH).

EXAMPLE l2 3B-Acetoxy-2a-Imidazolylcarbonyl-SOxo-IB-Cyclopentaneheptanoic Acid Methyl Ester, S-Cyclic Ethylene AcetalN,N'-Carbonyldiimidazole (I64 mg., 1.01 m moles) is added to a stirredsolution of 3B-acetoxy-2acarboxy-S-oxo-lB-cyclopentaneheptanoic acidmethyl ester S-cyclic ethylene acetal (358 mg., 0.96 m moles) in 4 ml.of dry THF at room temperature under nitrogen. The reaction mixture isstirred at 25C. under nitrogen for 2 hours. The solvent is removed undervacuum and the oily residue is dissolved in benzene, washed with water,saturated salt solution, dried over M21 80 and evaporated to drynessaffording 370 mg. of 3B-acetoxy-Za-imidazolylcarbonyl-Soxo- IB-cyclopentaneheptanoic acid methyl ester, S-cyclic ethylene acetal. fi f'2.00 (s, 3H), 3.67 (s, 3H), 4.00

(broad s, 4H), 4.44 (m, 1H), 5.20 (m, 1H), 7.17, 7.37, 8.20 (3H).

EXAMPLE l3 3B-Acetoxy-2a-Formyl-5Oxo-1B Cyclopentaneheptanoic AcidMethyl Ester, 5-Cyclic Ethylene Acetal A solution of lithiumtritertiarybutoxy aluminum hydride (120 mg., 0.47 m moles) in 3 ml. dryTHF is added dropwise to a stirred solution of3B-acetoxy-2aimidazolylcarbonyl-Soxol B-cyclopentaneheptanoic acidmethyl ester, 5-cyclic ethylene acetal (I05 mg., 0.235 m moles) in 2 ml.of THF at 25C. under nitrogen. After 3.5 hours, a thin layerchromatogram (5% acetone in chloroform) of an aliquot indicates thecomplete absence of the starting amide. The reaction is worked-up afteran additional one-half hour by adding it to a chilled mixture ofsaturated aqueous NaH PO and ethyl acetate, the THF present is removedunder vacuum, and the mixture is extracted with ethyl acetate. Theorganic extract is washed with water, aqueous salt solution, dried overNa SO and concentrated in vacuo to give mg. of3B-acetoxy-2a-formyl-5-oxolB-cyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal; A f'" 3.68, 5.78, 1052 8 2.07 (s, 3H), 3.70(s, 3H), 3.97 (s, 4H), 4.2 (m, 1H), 5.2 (m, 1H), 9.75 (d, .l=2, lH).

EXAMPLE l4 3B-Acetoxy-2a-Formyl-5Oxo-1B- Cyclopentaneheptanoic AcidMethyl Ester, S-Cyclic Ethylene Acetal To a solution of 372 mg. (l mmole) of 3/3-acetoxy- 2a-carboxy-5-oxolB-cyclopentaneheptanoic acidmethyl ester 5-cyclic ethylene acetal in 5 ml. methanol at 0 is added 2ml. of 0.5H NaOH dropwise. The mixture is concentrated to dryness undervacuum at 0C. Benzene 10 ml.) is added and concentrated under vacuumtwice to remove traces of water. Benzene (5 ml.) and pyridine (0.l ml.)are added followed by 1 ml. of oxalyl chloride in 2 ml. of benzene, withthe temperature maintained throughout at 0C. After 15 minutes themixture is concentrated to dryness, benzene added and the mixture againconcentrated to dryness. The residue is dissolved in 5 ml. of diethyleneglycol dimethyl ether (diglyme) and cooled to 78C. To the stirredsolution is added dropwise 255 mg. (l m mole) of lithium t-butoxyaluminum hydride in 5 ml. of diglyme maintaining the temperature at 78C.After 20 minutes the mixture is allowed to warm to 20C., poured ontocrushed ice and extracted with ether. The ether extract is washed withwater, saturated aqueous sodium chloride, dried over sodium sulfate andconcentrated to dryness, under vacuum. The residue consists of3B-acetoxy-2a-formyl5-oxol B- cyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal with physical properties identical with thoseof the material obtained from Example l3.

EXAMPLE l5 3B-Acetoxy-5-Oxo-2a-( 3-Oxol -Octenyl)- l B-Cyclopentaneheptanoic Acid Methyl Ester, S-Cyclic Ethylene Acetal Asolution of dimethyl 2-0xoheptylphosphonate 1 38 mg., 0.62 m moles) in 3ml. of dry THF is added over 3 minutes to a stirred suspension of sodiumhydride as a 50% oil dispersion (24.3 mg., 0.507 m moles) in 6 ml. ofTHF at 0C. under nitrogen atmosphere. A gelatinous precipitate of theylid sodium salt forms within 30 minutes. After an additional 30 minutesat C., :1 solution of 3B-acetoxy-2a-formyl-5-oxo- 1B-cyclopentaneheptanoic acid methyl ester, -cyclic ethylene acetal (185mg., 0.507 m moles) in 5 ml. of THF is added dropwise and the reactionmixture isallowed to warm to room temperature with stirring continued at25C. for 3.5 hours. A thin-layer chromatogram acetone in chloroform)indicates the complete disappearance of the starting material. Thereaction mixture is cooled to 0C. and added to chilled saturated NaH P0solution. The mixture is concentrated in vacuo to remove THF and isextracted with ethyl acetate. The latter extract is washed with aqueoussodium chloride, dried over MgSO, and evaporated in vacuo to provide 285mg. of residue which is chromatographed on g. of silica gel eluting with5% acetone in chloroform to provide 161 mg.BB-acetoxy-Zu-formyl-S-oxolB-cyclopentaneheptanoic acid methyl ester,S-cyclic ethylene acetal which is spectroscopically identical with anauthentic sample.

EXAMPLE l6 3-Acetoxy-2-( 3-Hydroxyl -Octenyl)-5-Oxocyclopentaneheptanoic Acid Methyl Ester, S-Cyclicethylene Acetal To asolution of 40 mg. of3-acetoxy-2-(3-oxo-loctenyl)-5-oxocyclopentaneheptanoic acid methylester, 5-cyclicethylene acetal in 1.5 ml. of methanol stirred undernitrogen at 0C. is added 0.4 ml. ofa solution of 17 mg. of sodiumborohydride in 2 ml. of methanol (3.4 mg. NaBl-L). After 30 minutes at0C. the mixture is added to 20 ml. of cold saturated aqueous NaH P0 andextracted with ethyl acetate. The latter extract is dried over Na SO,and concentrated to dryness to give 40 mg of 3-acetoxy-2-(3-hydroxyl-octenyl)-5- oxocyclopentaneheptanoic acid methyl ester, 5-cyclicethylene acetal as a mixture of hydroxy epimers on the octenylside chain. If desired the epimers may be separated at this stage bythin layer chromatography on silica gel (system 10% acetone inchloroform).

EXAMPLE 1? 3-Hydroxy-2-( 3-Hydroxyl -Octenyl )-5-Oxocyclopentaneheptanoic Acid, 5-Cyclicethylene Acetal To a stirredsolution of 30 mg. of the mixture of epimers of 3-acetoxy-2-( 3-hydroxyl-octenyl )-5- oxocyclopentaneheptanoic acid methyl ester, 5-cyclicethylene acetal obtained in the preceding example in 1 ml. ofmethanol at 0C. under nitrogen is added 0.4 ml. of a solution of 88 mg.of potassium hydroxide in 1 ml. of water. The yellow solution is kept at20-25C. for 3 hours. it is then added to cold saturated aqueous NaH PO10 ml.) and extracted with ethyl acetate. The latter extract is driedover Na SO and concentrated to dryness to give 28 mg. of 3-hydroxy-2-(3-16 hydroxy l -octenyl )-5-oxocyc1opentaneheptanoic acid, 5-cyclicethylene acetal as a mixture of hydroxy epimers on the side chain.The substances are separable on silica gel plates (system-benzene:dioxane: acetic acid: 20:20:l the most polar component (R 0.5) being thedesired one.

EXAMPLE l8 3-Hydroxy-2-( B-Hydroxyl -Octenyl )-5-Oxocyclopentaneheptanoic Acid (+)-Prostaglandin 1) A solution of 30 mg.of the epimeric mixture of 3- hydroxy-2-(3-hydroxy-l-octenylJ-S-oxocyclopentaneheptanoic acid, S-cyclicethylene acetal in 2 ml. of 50%aqueous acetic acid is kept at 20-25C. for 3 hours. It is thenconcentrated to dryness to give 28 mg. ofcrude3-hydroxy-2-(3-hydroxy-loctenyl)-5-oxocyclopentaneheptanoic acid,(prostaglandin E The product is purified by preparataive thin layerchromatography on silica gel (system-benzene:dioxane:acetic acid40:40:1) visualizing the components by water spray. The band, whichcorresponds to prostaglandin E, is eluted with methanol, the eluatefiltered, the filtrate concentrated to dryness and the residue taken upin chloroform. The latter solution is washed with aqueous NaH PO driedover Na SO and concentrated to dryness. Crystallization of the residuefrom ether'hexane gives (i)-prostaglandin E m.p. 1 10C. The syntheticmaterial has identical tlc mobility as naturally derived prostaglandin EVarious changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

l. 2a-Carboxy-3a-( l, l -dihydroxyethyl )-5- oxocyclopentaneheptanoicacid carboxymethyl ester, y-lactone 5cyc1ic ethylene acetal.

2. 2a-Carboxy-3a-( l-hydroxyethyl l 6-1 ,3-dioxolan-2-yl)hexyl]-5-cyclopentanone 5-cyclic ethylene acetal,'y-lactone.

3. 2a-Carboxy-3a-( l-hydroxyethyl)- l 6- formylhexyl)-5cyclopentanone,S-cyclic ethylene acetal, 'y-lactone.

4. 2a-Carboxy-3a-( l-hydroxyethyl 1 6R carbonylhexyl)-5-cyclopentanone,5-cyclic ethylene acetal, y-lactone, wherein R is halo.

5. 2a-Carboxy-3a-( l-hydroxyethyl)-5- oxocyclopentaneheptanoic acid,5-cyclic ethylene acetal, 'y-lactone, or a lower alkyl, benzyl or xylylester thereof.

6. The compound of claim 5 wherein the ester is the methyl ester.

1. 2A-CARBOXY-3A-(1,1-DIHYDROXYETHYL)-5-OXOCYCLOPHENTANEHEPTANOIC ACIDCARBXYMETHYL ESTER, Y-LACTONE 5-CYCLIC ETHYLENE ACETAL.
 2. 2 Alpha-Carboxy-3 Alpha-(1-hydroxyethyl)-1-(6-1,3-dioxolan-2-yl)hexyl)-5-cyclopentanone5-cyclic ethylene acetal, gamma -lactone.
 3. 2 Alpha -Carboxy-3 Alpha-(1-hydroxyethyl)-1-(6-formylhexyl)-5-cyclopentanone, 5-cyclic ethyleneacetal, gamma -lactone.
 4. 2 Alpha -Carboxy-3 Alpha-(1-hydroxyethyl)-1-(6-R2-carbonylhexyl)-5-cyclopentanone, 5-cyclicethylene acetal, gamma -lactone, wherein R2 is halo.
 5. 2 Alpha-Carboxy-3 Alpha -(1-hydroxyethyl)-5-oxocyclopentaneheptanoic acid,5-cyclic ethylene acetal, gamma -lactone, or a lower alkyl, benzyl orxylyl ester thereof.
 6. The compound of claim 5 wherein the ester is themethyl ester.